Greetings. My name is Joe, and I'll be your conference operator today. Welcome to Gritstone bio's fourth quarter and full year 2022 results conference call. Please note, this event is being recorded. At this time, I'd like to introduce George MacDougall, Director, Investor Relations and Corporate Communications at Gritstone. Please go ahead, sir. Thank you, operator, and thank you everyone for joining us for Gritstone bio's conference call to discuss our financial results, clinical, and business updates for the 4th quarter and full year 2022. With me on the call today from Gritstone bio are Andrew Allen, Co-Founder, President, and CEO; and Celia Economides, Executive Vice President and Chief Financial Officer. Joining us for the Q&A portion will be Karin Jooss, our Head of R&D. Today, after the market closed, we issued a press release providing our 4th quarter 2022 and full year 2022 financial results, as well as clinical and business updates. The press release is available on our website. I'd like to remind you that today's call is being webcast live via a link on Gritstone's investor relations website, where a replay will also be available after its completion. After our prepared remarks, we will open up the call for Q&A. During the course of this call, we will make forward-looking statements that are based on current expectations. These forward-looking statements are subject to a number of significant risks and uncertainties. Our actual results may differ materially from those described. We encourage you to review the risk factors in our most recent Form 10-K filed with the US Securities and Exchange Commission and available on our website. All statements on this call are made as of today based on information currently available to us. Except as required by law, we disclaim any obligation to update such statements, even if our views change. With that, let me turn the call over to Andrew. Andrew? Thank you, George, good afternoon, everybody. Let me begin by first thanking our entire team for the tremendous progress that we made in 2022. I'm proud of the work we've accomplished, which started seven years ago with the ambition to take the next big step in cancer immunotherapy. We're now just months away from seeing early data from the first randomized trial testing our hypothesis. This is an incredibly exciting time for Gritstone and a big year for personalized cancer vaccines. The prospect of opening up most common solid tumors to the survival benefits of immunotherapy lies immediately ahead of us at Gritstone, with preliminary proof of concept data from our randomized controlled GRANITE study in colorectal cancer expected in the fourth quarter of this year. If positive, these data could be transformational to the field and would encourage us to develop our platform in other common cold solid tumors such as ovarian, prostate, and breast cancers, which remain largely refractory to simple immune checkpoint blockade and still account for a huge number of deaths from cancer every year. The top-line data shared by Moderna and Merck in December of 2022 are very encouraging for our product concept. These data provide initial proof of concept for a neoantigen-based personalized cancer vaccine approach, albeit within the hot tumor context of melanoma. In total, randomized data from the three big players in the field, ourselves, Moderna, and BioNTech, are expected in 2023. As I mentioned at the outset, this is an exciting year for personalized cancer vaccines. Let's dive into our work in oncology. First, I'll address GRANITE, our fully individualized vaccine program. Let's step back and remind ourselves of the therapeutic hypothesis that underpins this program and the clinical data we've generated in support of it. Most patients with solid tumors have immunologically cold tumors wherein there is no evidence of immune system recognition of tumor neoantigens, no detectable neoantigen-specific cytotoxic T-cell response, and thus no T cell substrate for checkpoint inhibitors to work on, leading to their relative inactivity as therapeutics in such patients. Our original idea was, and our approach remains, to identify tumor neoantigens and build vaccines containing these antigens and then deliver them to patients alongside checkpoint inhibitors to induce strong neoantigen-specific CD8+ T cells, also known as cytotoxic T cells. Once administered and generated, these T cells could then traffic to tumors, meet their antigen, proliferate, and kill tumor cells, leading to clinical benefit. This approach was described in our Nature Medicine paper published in August of 2022. We've been diligently working on each step in this chain and have shown positive results in patients with advanced disease, with a focus on colorectal cancer. Specifically, we have shown the following. First, we can predict tumor neoantigens with high accuracy, a positive predictive value of over 75% at this point, and we continue to refine and improve our prediction model continuously. Secondly, in patients with no detectable neoantigen-specific T cells at baseline, our simple vaccination schedule elicits strong responses, primarily CD8+ T cells, which can be readily detected in blood using traditional assays such as ELISpot. Thirdly, these neoantigen-reactive T cells traffic into tumors and proliferate, changing the T cell composition of the tumors and, critically, turning cold tumors into hot ones. Fourthly, these T-cell responses are associated with tumor cell destruction, as measured by reductions in traditional biomarkers such as CEA and CA 19-9, often elevated in advanced colorectal cancer patients, as well as parallel reductions in circulating tumor DNA or ctDNA, an emerging biomarker of value to immunotherapy drug developers. These molecular responses have been observed in approximately half of the third-line colorectal cancer patients we treated. Finally, molecular response was then associated with extended overall survival, such that molecular non-responders experienced a median overall survival of 7.8 months, exactly as expected in this context. Whereas molecular responders have not yet reached median overall survival, although it will exceed 22 months. Having observed the success of this approach in a single-arm study in advanced disease, we launched our randomized controlled phase II/III study in newly diagnosed metastatic colorectal cancer patients, whereby patients are randomized to receive maintenance therapy with standard of care 5-fluorouracil, or 5-FU, plus bevacizumab or 5-FU plus bevacizumab plus our GRANITE immunotherapy. This is a registrational quality study discussed with FDA back in August 2021, and we are enrolling 80 subjects in the open label phase II component with preliminary data expected in the 4th quarter of this year. We anticipate sharing both ctDNA and progression-free survival data evaluated using both RECIST and iRECIST criteria on patients completing at least 4 months of treatment. We plan to discuss the results with FDA in the first half of 2024 to align on the appropriate primary efficacy endpoint and then move into the phase III component of the trial. On a related note, I'd like to acknowledge our industry, the clinicians, the patient advocates, and the regulators for the work currently being done to evaluate and corroborate the association between molecular response and extended overall survival. The draft guidance the FDA issued in mid-2022 regarding ctDNA as a potential predictor of response among early-stage cancer patients represented an important step forward. The work being done across the industry to incorporate ctDNA into drug development and patient and treatment selection is ongoing. The burgeoning data and rapid adoption of ctDNA across healthcare sectors gives us conviction that we're following the right path for Gritstone and for patients alike. With GRANITE, note that this trial, which again is in a common and cold tumor type, potentially opens the door to a transformation in cancer immunotherapy. Put otherwise, if GRANITE works in colorectal cancer, one of the hardest to treat cancers, it is reasonable to think it will work in many other solid tumor types. We believe the generation and/or amplification of potent neoantigen-specific CD8 cytotoxic T cells is always a good thing for cancer immunotherapy and for cancer patients, and that potentially vaccines like GRANITE may become a foundational component of solid tumor immunotherapy. If we're successful in this endeavor, biomanufacturing of personalized vaccines at scale will be a critical requirement. Importantly, recall that we manufacture our own vaccines at our GMP biomanufacturing facility in California. Our decision to manufacture in-house has offered us many strategic benefits since we built the facility several years back. Our manufacturing process continues to improve in efficiency and capacity as we plan to scale out for phase III with an eye to commercial scale. To SLATE, which is our product platform that leverages the same biology as GRANITE, but seeks to do so in an off-the-shelf manner. Off-the-shelf vaccines are attractive in that they can be administered rapidly upon patient selection. The key issue for the field has been to identify shared tumor-specific antigens that can be included within an off-the-shelf product. The commonest shared neoantigens derive from mutant KRAS proteins, and this is where we began our SLATE program a few years ago. In September of last year, we shared initial results from the phase I/II study of KRAS-directed SLATE in late-line patients. Just as in the GRANITE phase I/II study, we observed induction of neoantigen-specific CD8+ T cells across all tumor types evaluated in the study, including metastatic microsatellite stable colorectal cancer and non-small cell lung cancer. Also, as in GRANITE, we saw molecular responses in roughly half of evaluable patients. The largest single group of patients had advanced non-small cell lung cancer, all refractory to checkpoint blockade. In this group, molecular responses were associated with approximate doubling of overall survival compared with subjects who didn't experience molecular response. This is very consistent with what we observed in GRANITE, and the symmetry of these observations across products and across tumor types is suggestive of consistent biology and true efficacy signal. Following the same playbook as with GRANITE, our next step is to verify findings in a randomized controlled trial in newly diagnosed metastatic patients. We're launching such a study later this year. SLATE is a fascinating program that will diversify over time as more shared tumor antigens are identified and included in our vaccines, enabling applications beyond just mutant KRAS patients. Underlining the notion that stimulation of tumor antigen-specific T cells is likely always a good thing, we've recently begun a clinical collaboration with Dr. Steve Rosenberg at the National Cancer Institute, combining his mutant KRAS-specific cell therapy with our mutant KRAS-specific vaccine. We're excited by the science behind this approach and believe there's significant potential for it to extend the benefit of vaccine and cell therapy to a potentially broad set of patients. Combinations of our vaccine with small molecule mutant KRAS inhibitors may also make sense, and this is an area of interest at Gritstone. On the infectious disease side of our business, we continue making strides in putting clinical data onto the self-amplifying mRNA or samRNA platform via CORAL, our program evaluating vaccines against SARS-CoV-2. Through our 3 phase I CORAL studies, we continue to demonstrate the potential broad utility of samRNA to serve as a next-generation platform vector. In August 2022, we reported 6-month neutralizing antibody data from the first 2 cohorts of our ongoing CORAL-BOOST trial, which is evaluating our samRNA vaccines as a boost following Vaxzevria and/or mRNA primary series. While numbers are small, results showed in all observable patients, the strong neutralizing antibody responses originally reported in January 2022 persisted without decay up to 6 months. In the fourth quarter, we were notified that our NIAID-sponsored CORAL-NIH study had completed enrollment. We also shared additional interim data updates from our CORAL-BOOST and CORAL-CEPI studies. These additional data demonstrated robust and potentially durable neutralizing antibodies along with CD8+ T-cell responses. Enrollment in the CORAL-CEPI study is now complete. We plan to share further data from these studies at the ECCMID Conference in Copenhagen in April. samRNA is rapidly emerging as a well-tolerated, scalable, and widely applicable platform technology, likely with distinct characteristics versus first generation mRNA. We believe the data we're generating against SARS-CoV-2 provide clinical proof of concept for the continued application of samRNA across a wide range of infectious diseases. Outside of SARS-CoV-2, our partnership with Gilead to develop a vaccine-based curative HIV immunotherapy treatment remains active and ongoing in a phase I study. Results from a preclinical study in non-human primates within this program were presented at CROI just last month, demonstrating strong and durable viral antigen-specific T-cells responses, further augmented by immune checkpoint blockade. In addition to these clinical stage programs, we have exciting preclinical projects ongoing, including development of an optimal immunogen for a therapeutic human papillomavirus vaccine that is supported by the Gates Foundation. We're also researching an influenza vaccine as well as a new combination vaccine against multiple respiratory viruses. We look forward to sharing additional updates on our infectious disease programs and research throughout the year. Finally, I'd like to address some recent developments related to our intellectual property position, which we believe to be a strong asset for Gritstone. In late 2022, we received two United States patents related to samRNA. One includes claims covering Gritstone's individualized cancer vaccine candidates within the GRANITE program. The second includes claims covering antigen-encoding samRNA vectors in general and has broad applicability across Gritstone's candidates in oncology and infectious disease. Additionally, we received recently a third U.S. patent directed to Gritstone's proprietary chimpanzee adenovirus, or ChAd vector, which is modified to improve viral production. We use ChAd to prime within our oncology programs. It is a key asset in our GRANITE strategy to turn cold tumors hot. We view these patents as critical parts of a competitive moat around our therapeutic strategies. These recent patents further strengthen our IP position, which also includes our EDGE platform, key for accurate cancer neoantigen prediction. I'll now turn over to Celia, who'll provide more color on our financial results for the fourth quarter and for the full year of 2022. Celia? Thank you, Andrew. Good afternoon, everyone. Gritstone ended 2022 with $185.2 million in cash equivalents, marketable securities, and restricted cash. These include net proceeds of $42.4 million from a private placement secured in October 2022, and $19.6 million in net proceeds from utilizing our ATM offering program. We also secured an $80 million credit facility from Hercules Capital and Silicon Valley Bank in July 2022 and drew $20 million of that total at closing. Throughout the year, we also implemented several capital conservation measures that helped to extend our runway while enabling us to pursue our corporate goals. We currently have cash runway into the second quarter of 2024, with multiple potential avenues to secure additional capital in 2023. These include, but are not limited to, drawing down additional funds from our existing credit facility, establishing new or expanding existing collaborations, and other non-dilutive funding sources, such as a potential $40 million milestone payment from Gilead on our HIV cure partnership. Turning to our full year 2022 operating results, our reported research and development expenses were $111.4 million for the year ended December 31, 2022, compared with $97.5 million for the year ended December 31, 2021. The increase in R&D costs was primarily due to increases in personnel-related costs and clinical trial expenses. We reported that general and administrative expenses were $29 million for the year ended December 31, 2022, compared with $25.9 million for the prior year. The increase was primarily attributable to an increase in personnel-related costs and an increase in outside services to support our ongoing operations. We also reported that collaboration, license, and grant revenues were $19.9 million for the year ended December 31, 2022, compared to $48.2 million for the prior year. Our 2022 revenues include $1.6 million in collaboration revenue related to the Gilead collaboration agreement and $7.7 million in collaboration revenue related to the 2seventy bio agreement. $9.5 million in grant revenue related to the CEPI agreement, and $1.2 million in grant revenue related to the Gates agreement. The net loss was $31.3 million for the fourth quarter of 2022, compared with $29.8 million for the same period last year. The net loss was $119.7 million for the full year 2022, compared with $75.1 million for the same period last year. Finally, as of December 31, 2022, Gritstone had 86,894,901 shares of common stock outstanding and pre-funded warrants outstanding to purchase 13,573,704 shares of common stock at a nominal exercise price of $0.01 per share and 13,274,923 shares of common stock at an exercise price of $0.0001 per share. This brings the total pre-funded warrants outstanding as of December 31, 2022 to 26,848,627. I'll now turn the call back over to Andrew for some closing remarks. Andrew? Thank you, Celia. Gritstone was formed to pursue a big idea and take a bold approach to driving a potentially transformative novel product class. Over the 7 years since our founding, we've carefully curated and advanced our set of capabilities and technologies with the aim of driving more potent and durable tumor-specific immune responses and then infectious disease immune responses. We now sit at the threshold of proving out our neoantigen approach in metastatic colorectal cancer, an accomplishment that could open up cold, solid tumors. Additionally, we're pioneering a novel technology that could represent the next RNA platform approach against infectious disease. We look forward to what will be an exciting year ahead for Gritstone and to continuing to share our findings with you throughout that time. With that, I'd like to thank you all for joining us today. I'll now turn the call over to the operator for questions. Operator? Thank you. Ladies and gentlemen, if you would like to ask a question, please press star one on your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we poll for questions. Our first question comes from the line of Marc Frahm with TD Cowen. Please proceed. Thanks for taking my questions. Maybe just to start off with, Andrew, as we look towards that data in Q4, you know, given the size of the dataset, what type of difference in ctDNA responses do you think is, you know, the kind of minimum that's likely to predict ultimately as some data fully matures, a PFS, you know, significant PFS difference? I would change the question slightly because what we care about is not the PFS difference. What we care about is an OS difference. That obviously is the goal here, really. Of course, that is the efficacy endpoint that matters. It's the only one that matters aside from quality-of-life-type endpoints. Living longer, functioning better, and feeling better are the sort of classic trio. It really is about overall survival, and ctDNA appears to be a better surrogate with novel immunotherapies to that endpoint. It's not been well-characterized in this context, as you know. It's been well-characterized in the adjuvant setting, identifying patients at high risk of disease recurrence, and it seems to track with outcome extremely well in that setting. It's increasingly being validated in lung cancer immunotherapy, and Friends of Cancer Research have published some data showing again that ctDNA response correlates with overall survival. Their data suggested that the nuances were not that important. You know, they looked at different thresholds of percentage reduction. They looked at different techniques for determining whether it's a mean or a median, for example. The evidence from their manuscript was that actually it didn't matter that much, which is good 'cause strong signals should obviously shine through and make small tweaks to assessment, frankly, rather irrelevant. We're doing this for the first time in the setting of metastatic colorectal cancer, we don't really know the answer to your question. We've powered the study to detect at least a 20% difference in ctDNA response rate between the two arms. It doesn't anchor on an absolute value, it anchors on a delta between the two arms, which I think obviously is reasonable. I don't know that 20% is the right number. I don't know obviously what we're going to see. We could see a much bigger number. How that mathematically correlates with overall survival is hard to know at this point, or it's impossible to know at this point. What we've learned from others is that, you know, as you might expect, and as is true with most tumor markers, if you start a new therapy and the markers go up, that's bad. If they stay flat, that's good. If they go down, that's best. I think that's likely to be true here, as we've discussed. 20% is what we're statistically looking for, but I think it's an open question as to how changes will actually correlate with overall survival. Okay. I think that's very helpful. Then maybe for Celia, just given what's going on in the wider market with one of your lenders, can you remind us if there are any clauses associated with that might allow them to accelerate payback on the loan? Thanks, Marc. The loan is actually with both Hercules and SVB, with the majority of it actually being with Hercules Capital. There is a financial covenant that kicks in, which you can read in our 10-K, that does kick in April of this year. We have to have 55% of the outstanding loan on our balance sheet. We've only drawn down $20 million at this time. Okay. Fair enough. Thank you. Our next question comes from the line of Ted Tenthoff with Piper Sandler. Please proceed. Great. Thank you very much, and thank you for the update, everybody. My question is on SLATE. Again, kind of digging in a little bit deeper in terms of how you intend to advance and what that product could look like. I'm sorry, what that next study could look like with the KRAS product. Thanks. Yeah, thanks, Ted. We haven't disclosed the details of that study, but it will follow the same playbook, as we've followed with GRANITE, as you might expect. Clearly, vaccinating subjects, as a last line therapy and end of life therapy, essentially, is never the optimal place for a vaccine-based immunotherapy. Everyone, I think, will acknowledge that. Of course, that's where you need to begin in order to demonstrate safety and earn your way to move upstream. I think we've done that with GRANITE. I think we've now done that with SLATE. We are intending to move upstream to a much earlier line of therapy, likely newly diagnosed metastatic subjects. One of the key questions for an off-the-shelf product is how to deliver as many antigens as possible that are relevant to each patient. Of course, the beautiful thing about the personalized vaccine is you're delivering, in our case, you know, 20 candidate neoantigens, of which we've got data to suggest that typically between 12-15 of them are real neoantigens. That is a strength of a product because the same as with small molecule drug therapy for viruses, you want multiple lines of attack on a highly mutable target to reduce the probability of acquired resistance. That's the same for viruses as it is for tumors. We just think about multiple lines of attack to reduce acquired resistance. With SLATE, how can we deliver multiple antigens, to try and achieve the same goal? KRAS obviously is a very good shared target, but it is one target, and therefore, what can we add in that will enable us to have attack, T-cell attack on KRAS mutant neoantigens, plus perhaps some other tumor-specific targets. That's the work that obviously we do pretty extensively at Gritstone. You know, we have a large team in Cambridge, Mass. This is our tumor epitope discovery group. They have continued to iterate on our prediction model over the last several years since we last published from the platform. One of the key areas they're looking at is additional shared tumor antigens. It's an important question, and it is one we're paying a lot of attention to. Today is not the day for us to reveal more. We will do so later this year as we disclose details around that SLATE randomized trial. Okay. Thanks, operator. I think we're ready for the next question. Thank you, Ted. Our next question comes from the line of Mayank Mamtani with B. Riley Securities. Please proceed. Good afternoon. Thanks for taking our questions, and congrats on the progress. Just a couple of quick follow-ups. In the phase II/III regimen, the importance of having 2 ChAd shots, you know, if we compare against the phase I data set, could you just talk about that? Secondly, did you say what the standard of care molecular response you're expecting? I just have one final question. I didn't specify. We think it'll be low, but as I said, the study is powered to detect a difference, rather than being focused on an absolute value. Over 20% difference between the 2 arms, I think is likely to be meaningful. In terms of the rationale for administering a second dose of the adenovirus, let me hand that question over to our adenovirus guru, Karin Jooss, our Head of R&D. Karin Jooss, would you like to take that one? Yeah, Thank you, Andrew. Great question. We have assessed in non-human primates whether we could revaccinate non-human primates after several months with the chimpanzee adenovirus vector. The reason was we knew that adenovirus is highly biased to driving high CD8+ T-cell responses, and this is what we after with our GRANITE vaccine. I had done in the past studies, assessing the interval needed to be able to come back with the adenovirus vector, because once you vaccinate with this vaccine platform, there is neutralizing antibodies being generated against the code proteins. We introduced in non-human primates after 6 or 7 months, then also after 4 months, the adenovirus vector, and we saw a very, very strong boost effect, specifically CD8+ T cell boost effect. This is what we introduced in our initial GRANITE study. This is what we added to the protocol of GO-010. We are after kicking the CD8+ T cells up to very high titers with the second administration of the ChAd. Understood. Thank you. Then on the regulatory scenarios that could exist after achieving this data in 4Q, could you maybe comment on, is there anything that you're specifically looking to learn from the Moderna Merck situation, you know, given that you will have placebo control data, you will have a number of these translation markers, you know, correlating with survival metrics. Could you just kind of high level sort of commentary on how you're thinking about engaging with the FDA after fourth quarter. Merck Moderna obviously is potentially useful. They haven't published anything on their personalized cancer vaccine program. There's been a few poster presentations at various meetings, so we don't really know anything about, you know, the key attributes. How do they do neoantigen selection, the quantifying the strength of the T-cell response, the diversity, the phenotype of those cells, the numbers of neoantigens being recognized pre and post-vaccination. Any of that information would obviously be helpful, and we'll see whether that's disclosed. A simple answer is we don't know much about their data, and we are kind of just waiting like everybody else to see what's published and presented hopefully in short, in short order. In terms of the agency, obviously, we all have the collective goal of trying to improve outcomes for patients with metastatic colorectal cancer, which remain dismal with a median survival of no more than two years for a typical, newly diagnosed patient. As we all know, no real benefit from immunotherapy. We've had a constructive dialogue with the agency through the development of this program. You know, we started talking to them way back before we were in the clinic around things like sequencing approaches and how that would be regulated. We solicited their input to the design of our biomanufacturing facility. We've had a good, built a good relationship with the agency. When we spoke to them last on this topic, which was in the summer of 2021, we aligned on the design of this phase II/III program, and it's a sort of traditional program in that there is a phase II, a randomized phase II, and we will learn a lot, and we will use the insights from the phase II to inform the design of the phase III. The key issue on the table will be what's the primary efficacy endpoint for phase III? That conversation we anticipate will happen in the first half of 2024. The obvious endpoint is overall survival. It's unambiguous, it's internationally accepted, and of course, it's the one that counts. In terms of timing, unfortunately, this is a disease where you don't have to wait that long to obtain survival data. As I say, median survival is around 2 years. whereas a PFS study, you know, would be around 1 year, median PFS, 11 or 12 months, something like that. It's not a big difference between a surrogate endpoint like PFS and the hard clinical endpoint of overall survival. OS is, I think, the default. It's possible that a form of PFS might be a good surrogate, but we don't really know that today. With our kind of immunotherapy, as I've mentioned previously, the major concern is pseudoprogression. That we drive T cells into lesions which get bigger for a good reason, which is that T cells are proliferating. The assumption of the RECIST rules is that lesions getting bigger is bad 'cause it's tumor cell proliferation. That obviously is an assumption that was developed when RECIST was developed for cytotoxic chemotherapy. It worked for targeted therapeutics, but obviously has just theoretical challenges and then practical observed challenges if you apply that principle to a therapy designed to expand lesion size. RECIST is a problem. I think the agency kind of knows this. The question is whether the modification to RECIST called iRECIST, that permits essentially one cycle of so-called pseudoprogression, whether that adequately addresses the nature of efficacy that we observe with our vaccine-based immunotherapy. We simply don't know the answer, and that's why we're collecting the data in the phase II study. That will be a part of the discussion. Obviously, there's much interest in ctDNA. It is clearly something that a lot of people are working on. you know, our view is that it will become an accepted surrogate in metastatic disease. The question is when will that come? Obviously, the agency needs to see a body, a significant body of validating data that so far has not been generated and presented. There is uncertainty as to when that when they'll cross the line and start to accept ctDNA change as a surrogate endpoint. you know, I think they're holding the bar appropriately high. Obviously, we don't want to approve drugs with endpoints that actually lead to approval of drugs that ultimately don't extend survival. You know, parenthetically, we've seen quite a bit of that with checkpoints and the use of RECIST as a basis for accelerated approvals. Hence the advisory committee last year on that notion of dangling approvals, some of which led to sponsors withdrawing approvals. It's a complicated topic. It's one that can only really be answered with data. We're generating the data, and we'll be discussing those data with the agency first half of 2024. As I say, there's always gonna be an endpoint for phase III that we'll be very happy with, which would be overall survival. The question on the table is whether there's a proximal endpoint that might enable an earlier, perhaps accelerated approval. More to come on that topic. Thanks for the question. Thank you. Looking forward to it. Yep. Our next question comes from the line of Arthur He with H.C. Wainwright. Please proceed. Good afternoon, Andrew and team. This is Arthur for Shaw. Thanks for taking my question. I apologize 'cause I get on the call late. I apologize if this topic has been discussed. Regarding your COVID vaccine program, I noticed there's a data update expecting the second quarter of this year. Could you tell us what kind of data result we can expect here? Sure. Yeah. Thanks for the question, Arthur. It that question has not been asked before, so happy to take it. The key issue with self-amplifying mRNA is whether it is better than mRNA. If it isn't, then obviously I think we have some pretty good mRNA vaccine players out there. They are not perfect. One of the key challenges has proven to be the durability of mRNA vaccine-elicited neutralizing antibodies. If you had a vaccine platform that generated antibodies that were more persistent, that I think would be a materials advance because it would reduce the need for repeated boosting, which obviously has bedeviled the field of mRNA vaccines, as we all know. We have early data in the boost setting from our U.K. study suggesting that samRNA elicits neutralizing antibodies that have high stability in the blood, meaning that the concentration of antibody doesn't materially change over 6 months. That's what we observed in a small number of subjects. Therefore, we need to confirm that finding in a much larger end, ideally of subjects who have not been previously primed and vaccinated, but are vaccine naive. That's the data set that we've been generating in South Africa in our CEPI-funded study of several different SARS-CoV-2 constructs in a vaccine-naive population in South Africa. 6-month antibody data is what we anticipate sharing at the ECCMID conference in Copenhagen in April, and that will be from over 100 subjects. We're looking at some different dose levels, slightly different types of subjects. Some are virus naive, or we're trying to determine virus naive, which can be a little bit challenging, but let's label them virus naive versus clearly virus convalescent folks. They're all vaccine naive. That's a very important data set, and that is key I think to the new data coming in April of this year. The second question around differentiation perhaps will relate to the dose. Here there's a growing interest in the notion of multi-pathogen vaccines. The one that's much talked about is the idea of a single vaccine that protects people over 60 against 3 different viruses: RSV, influenza, and SARS-CoV-2. Can I put all 3 together? Obviously the question is: What will the benefit, in other words, the immunogenicity look like? What will the reactogenicity look like? You know, how well tolerated will such a vaccine be? The challenge with some of the products is that at the full dose, you know, there's a clearly acceptable amount of reactogenicity. If I drop the dose, perhaps by a third to allow three equivalent or three different pathogens in the same product, dropping the dose actually leads to meaningfully reduced immunogenicity, which obviously is not what you want. That's definitely moving in the wrong direction. So dosing and the immuno-reacto ratio becomes very important for the platform. This is where self-amplifying mRNA may have an advantage because it does make copies of itself, which permits relatively low doses to be used, as we've shown. The interesting question becomes: Do we see good immunogenicity at low doses, you know, as low as 3 or 5 micrograms, such that one could think about putting 3 of those doses together into a 15 microgram product with acceptable reactogenicity? I think the immuno-reacto profile of samRNA looks a bit different from what we've seen so far from mRNA. The just the numbers are different. Of course, again, be looking out for those data in this data set coming at ECCMID. Those are 2 potential points of key differentiation for self-amplifying mRNA versus mRNA, and I think that's what you should be looking for. Oh, that's awesome. Thanks for the color, Andrew. My second question actually allude to the multi-agent vaccine. In your plan, are you guys still pursuing COVID, flu, RSV, triple A vaccine by yourself or, you are only pursuing that with a partner? We're interested in that product concept for sure. There are obviously quite a few things we can do at a research level. We're well equipped to do those. Obviously, if we have good data, then that might be something a partner potentially would be interested in. Certainly we are pursuing that product class internally, initially at the research level, as you might anticipate. Gotcha. Thanks for taking my question. Congrats on the progress. Thank you. Our next question comes from the line of Corinne Jenkins with Goldman Sachs. Please proceed. Yeah, good afternoon, everyone. Maybe just a couple from me. With this fourth quarter update for GRANITE, just how many patients should we be looking for? I know we don't have a great sense of the magnitude of ctDNA benefit, but as you think about clinical thresholds to move forward with the program, what would kind of be your base case expectation? What would make you really excited? What would be kind of the less exciting outcome? Thanks, Corinne. The sample size for the phase II component is 80, obviously the study's enrolling well, we anticipate data from a meaningful fraction of those subjects at year-end. The key here is that you need 4-month data. That's the constraint on the sort of total quantum of data this year, which is the requirement for 4-month data. The reason we need 4-month data is that we have observed, even in 3rd line, and we've shown these data, we observe a pseudo-progression, not infrequently, which means that markers can be going up at the 6, 8-week time point, and scans can show lesion expansion at that time point, which actually is pseudo-progression because subsequently everything comes down. Obviously showing 2-month data is potentially uninformative. 4-month data, usually all of those events have occurred in the past, and it has become clear by 4 months the trajectory for that patient. 4-month data on a meaningful fraction of the 80 in Q4 of this year. In terms of magnitude of ctDNA response, as I mentioned earlier, we're powered to find a 20% delta. Obviously, the higher the delta, the more excited we will be because again, I think it's truism that going down is good and the more people you have going down and the further down they go and the more durable that decline in their ctDNA, the better. It is a sliding scale. You know, greater frequency, depth and durability are all good. We don't yet have enough insight into how that correlates with overall survival to sort of think about boundaries, but just simply a qualitative statement, I think that more of that is a good thing. That's helpful. Thanks. With the SLATE candidate that you're moving forward with, it sounds to me like it's slightly different versus the one we saw at ESMO. As you thought about updating that for next trial, just what were you trying to optimize for, and how do you think you've delivered that with this newer candidate? Yeah. We have tried to optimize, 'cause obviously one of the beautiful things about immunotherapy and the fact that we make our own products is that we can practice real translational development whereby we observe in humans and patients the outcomes, the effects of a particular vaccine, and we can then quickly iterate on it and then hopefully improve it, make it, and put it back in the clinic. It's true, you know, bed to bench, back to bed, biology and drug development, which is pretty exciting. You've seen this with SLATE. If you remember, we had a version 1 of SLATE that contained KRAS mutations, but also some additional shared antigens. What we observed there was that the magnitude of the immune response to the KRAS mutations was not as strong as we anticipated based on preclinical testing and on our GRANITE data. We dissected that out and realized that we actually had included an immunodominant antigen in the vaccine, which was a great antigen, but actually rare. Therefore, it wasn't relevant to most patients. It was presented by a common HLA allele, and so many patients were making really strong immune responses to this dominant antigen. Those immune responses were useless because the tumor didn't have the actual mutation. The net effect was to actually then reduce the strength of the KRAS specific response, which is the one the patient needed. This was obviously a novel observation. No one had really understood the notion of a hierarchy of antigenic dominance within human cancer neoantigens. This was a new observation, but an important one, and it was actionable. We modified the vaccine to remove that rare but dominant antigen, and we made a KRAS dedicated product. That's what we showed more data on at ESMO last September in Paris. We did indeed see a strong immune response to the modified vaccine exactly as we had intended. The key issue, as I mentioned earlier, is that we're still delivering a single neoantigen, and you just have to worry about acquired resistance. The best way that we can deal with that is to deliver additional antigens relevant to the patient, and that's the key term. It's not enough, obviously, just to put in any old antigen. It has to be relevant to that patient's tumor. That's the interesting question, what are those other antigens that will be relevant to a patient with a KRAS mutation? How do I capture those in a vaccine in a form that enables the patient to mount now a strong immune response to multiple antigens, which is likely to reduce the frequency and tempo of acquired resistance, all things being equal. That's the biological problem as we framed it, and we think we've got a good solution to that, and we'll be talking about that more in due course, as I say, as we start to prepare for launch of that study. Maybe just a quick follow-up on that, because as you said, you had the p53 there, and that didn't work great. How confident are you that you've been able to find the right additional antigens to go forward with this next generation product? We're confident, because obviously we've been learning a lot about how to encode antigens within our vaccines. We've been learning a lot about antigens, obviously, as we continue to study human tumors in great depth. As I mentioned earlier, we have a large team in Cambridge that does work, using sequencing, but also this sophisticated mass spec technique where you literally observe peptides presented on the surface of tumor cells, and you can actually quantify them. You can do quantitative mass specs, and you can kinda count the number of HLA peptide complexes on the surface of human tumors, and you can do that for different antigens and different HLA alleles, and that probably relates to this dominance phenomenon. We think we've got a way of assessing that outside of a clinical trial, just from tumor samples. Then, of course, we design accordingly and then test it again back in humans. Again, this iterative loop. I think, you know, long term, if you wanna deliver good neoantigen and cancer tumor antigen vaccines to large numbers of patients cheaply, the off-the-shelf product obviously is where we need to end up. We've got a lot to learn still, but I think this is a game that really is worth playing hard, and the winners, I think, will be those who figure it out and deliver these multi-targeted products in an off-the-shelf format to huge numbers of solid tumor patients. These products are obviously a lot cheaper to make than personalized products. That's obviously one of the key attractions here. Yeah. Thank you. Thanks, Corinne. Thank you. Ladies and gentlemen, there are no further questions at this time. This will conclude today's conference. You may disconnect your lines. Thank you for your participation.